Brain tumors are a leading cause of cancer deaths in people under the age of 35. An important concept in our understanding of brain tumors is that the neoplastic cells may arise from undifferentiated neuroectodermal cells (Rubinstein, L. J. J. Neurosurg 62: 795-805 (1985)) .
At the gastrula stage of central nervous system (CNS) development, neuroectoderm, forming the neural plate is derived from ectoderm which has been induced by underlying mesoderm. (Spemann, H. Yale University Press 1938)). The neural plate then folds, in the process called neurulation, to form the neural tube. The cells of the neural tube are the precursors for the major differentiated cell types in the central nervous system: astrocytes, oligodendrocytes, and the various types of neuron (Sauer, F. C. J. Comp. Neurol. 62: 377-405 (1935)). The cells of the neural tube may also be the precursors to neoplastic cells which form brain tumors.
Recent success in "tagging" individual CNS precursors and their daughter cells, either through infection by a marker-bearing retrovirus or by injection of stable, specific dyes and enzymes, has shown that neurons and non-neuronal cells (i.e., glia cells) are often derived from a common precursor. In retina a common precursor for neurons and the Mueller glial cell exists very late in development (Holt, C. E., T. W. Bertsch et al., Neuron 1: 15-26 (1988); Turner, D. L. and C. L. Cepko, Nature 238: 131-136 (1987); Wetts, R. and S. E. Fraser, Science 239: 1142-1145 (1988); a common precursor for different neuronal and glial cell types has also been demonstrated in cortex and tectum (Luskin, M. B., A. L. Pearlman et al., Neuron 1: 635-647 (1988); Price, J. and L. Thurlow, Development 104: 473-482 (1988); Walsh, C. and C. Cepko, Science 241: 1342-1345 (1988)).
Tissue culture systems have provided additional information about the differentiation potential of CNS stem cells. Single-cell microculture of embryonic day 14 rat forebrain has produced clones containing both neurons and glia (Temple, S. Nature 340: 471-473 (1989)). Analysis of a later precursor in the glial differentiation pathway has established specific factors influencing differentiation to oligodendrocytes or type II astrocytes (Raff, M Science 243: 1450-1455 1989)). Cell lines established by immortalization of CNS stem cells also reflect features of the stem cell and can differentiate along both the neuronal and glial pathways (Cepko, C. L. Ann. Rev. Neurosci. 12: 47-65 (1989); Frederiksen, K. et al., supra (1988)).
Antibodies have also proven useful for analyzing stem cells. For example, antibodies A2B5 (Raff, M. C. supra 1989) D1.1 (Levine, J. M., L. Beasley et al., J. Neurosci 4: 820-831 (1984), Rat 401 (Hockfield, S. and R. McKay, J. Neurosci 5: 3310-3328 (1985), and antisera against the intermediate filament vimentin (Bignami, A., T. Raju et al Dev. Biol 91: 286-295 (1982); Federoff, S. Molecular Bases of Neural Development (1985); Tapscott, S. J., G. S. Bennett et al., Dev. Biol. 86: 40-54 (1981) bind to antigens enriched in the proliferative zone of the neural tube. However, A2B5 and D1.1 recognize glycolipid epitopes and are less useful for analysis of gene expression. Vimentin, which appears transiently in brain development, is an ambiguous marker largely because of its promiscuous expression in many cultured cells as well as in a variety of developing and differentiated tissues (Traub, N. Intermediate filaments: a review. Berlin, SpringerVerlag (1985)).
The correlation between Rat 401 and proliferating cells in the developing nervous system has been examined in detail. Rat 401 was found to recognize a transient population of embryonic columnar epithelial cells and radial glial cells in many regions of the CNS (Hockfield, S. and McKay J. Neurosci. 5: 3310-3328 (1985)). The number of Rat 401 positive cells, their proliferative rate, and the developmental kinetics of Rat 401 expression relative to neuronal differentiation revealed that the immediate precursors to neurons are also Rat 401 positive (Frederiksen and McKay, J. J. Neurosci 8: 1144-1151 (1988)). Neither neurons nor glia in the adult brain express the epitope recognized by the Rat 401 antibody.
Although "tagging", tissue culture systems and antibodies have proven useful in analyzing neural precursor cells, there is still an incomplete understanding of the lineage of tumor development. For example, medulloblastoma, a common brain tumor of children, is associated predominantly with the cerebellum and brain stem. Medulloblastoma tumors contain cell types with differentiated characteristics of neurons, glia and muscle (Rubinstein, supra 1985; Coakham H. B., et al., J. Clin. Pathol. 38: 165-173 (1985); Velasco, M. E. et al., Surg. Neurol. 23: 177-182 (1985); Hayashi, K. et al., Acta Pathologica Japonica 37: 85-96 (1987); Cras, P. et al., Acta. Neuropathol 75: 377-384 (1988)).
Because of the presence of multiple differentiated cell types found in these tumors, Bailey and Cushing (Bailey, P. and H. Cushing, Arch. Neurol. Psychiatry 14: 192-224 (1925) proposed that rather than being multiple coincident tumors, they were derived from a multi-potential stem cell, which they called a "medulloblast". According to this model, a medulloblastoma tumor would result from uncontrolled proliferation and differentiation of the medulloblast. However, the hypothetical medulloblast has not been identified.
Due to the incomplete understanding of brain tumor development, there is currently no adequate assay for detecting brain tumors at an early stage in their development. In addition, there is no specific noninvasive method of treating brain tumors. Methods of detecting and treating brain tumors would be very useful.